Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) are both chronic autoimmune diseases.
RA is characterized by inflammation in multiple joints caused by an autoimmune reaction. This autoimmune reaction leads to pain in the joints and to erosion and destruction of the joint surface, which impairs their range of movement and leads to deformity and loss of function. The small joints of the hands, feet and cervical spine are most commonly affected, but larger joints such as the shoulder and knee can also be affected. In addition, RA is in many cases, inter alia, also associated with formation of rheumatoid nodules in the skin, vasculitis, fibrosis of the lungs and/or renal amyloidosis. RA can for example be diagnosed using x-ray imaging and determination of the presence of certain autoantibodies in blood samples of patients. Particularly, the presence of rheumatoid factor (RF, an autoantibody directed to the Fc region of human IgG) and anti-citrullinated protein antibodies (ACPAs), e.g. anti-cyclic citrullinated peptide (anti-CCP) is indicative for RA. Other diagnostical markers and tests are used for differential diagnosis, such markers and tests include for example the determination of the erythrocyte sedimentation rate (ESR), C-reactive protein, full blood count, renal function, liver enzymes and other immunological tests (e.g. antinuclear antibody/ANA).
In SLE the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage. SLE can affect any part of the body, but most often harms the heart, joints, skin, lungs, blood vessels, liver, kidneys, and nervous system. Diagnostic tests indicative for SLE include anti-nuclear antibody (ANA) testing, anti-phospholipid antibody testing and anti-extractable nuclear antigen (anti-ENA) assays. More specific tests are the anti-Smith and anti-dsDNA antibodies. Other tests routinely performed in suspected SLE are complement system levels (low levels suggest consumption by the immune system), electrolytes and renal function, liver enzymes, and a complete blood count.
The presence of autoantibodies against intracellular antigens such as components of large ribonucleoprotein (RNP) structures (e.g. ribosome or spliceosome) is characteristic for rheumatic autoimmune diseases such as RA and SLE.
Heterogeneous ribonucleoprotein complexes are present in the cell nucleus during gene transcription and subsequent post-transcriptional modification of the newly synthesized RNA (pre-mRNA). The hnRNP complex is formed of pre-mRNA and ˜30 proteins, among them the heterogeneous nuclear ribonucleoproteins hnRNP-A2 and -B1 as core proteins. hnRNP-A2 (also known as RA33) and hnRNP-B1 result from two different splice variants of the HNRNPA2B1 gene. Antibodies against hnRNP-A2 or -B1 (i.e. so-called anti-A2/-B1/-RA33 autoantibodies), have been shown to be more specific for RA than other markers, such as RF. The same is true for the closely related hnRNP-A1. anti-A2/-B1/-RA33 autoantibodies have also been found in samples of a significant fraction of SLE patients.
hnRNP proteins have been classified by sequence homology analysis into two subgroups, the A subgroup and the D subgroup. The A subgroup comprises hnRNP-A0, hnRNP-A1, hnRNP-A2, hnRNP-B1 and hnRNP-A3, whereas the D subgroup comprises hnRNP-A/B, hnRNP-D and hnRNP-DL (hnRNP-D-like).
hnRNP proteins and peptide fragments thereof are a major stimulator of autoimmunity in rats with pristane-induced arthritis and antibodies against hnRNP proteins and peptide fragments thereof are markers in SKG mice which have a RA-like disease and MRLpr and NZW mice which have SLE-like disease (Hoffmann et al., J. Immunol., 2007, 179: 7568-7576).
The most widely used system to classify RA is the American College of Rheumatology 1987 revised criteria for the classification of RA. (Arnett, F. C., et al., Arthritis Rheum. 31 (1988) 315-324). According to these criteria (known as ARA-criteria), a patient is said to have RA if the patient satisfies at least four of the following seven criteria, wherein criteria 1-4 must be present for at least six weeks: 1) morning stiffness for at least one hour, 2) arthritis of three or more joint areas, 3) arthritis of hand joints, 4) symmetrical arthritis, 5) rheumatoid nodules, 6) serum rheumatoid factor (“RF”), and 7) radiographic changes. These criteria have a sensitivity and specificity of approximately 90%.
The most important biochemical marker generally accepted (see the above ARA-criteria) and aiding in the diagnosis of RA is the rheumatoid factor (RF) as detected in serum.
The detection of anti-CCP (cyclic citrullinated peptide) antibodies and interleukin 6 for diagnosing RA has been described in EP 1 700 129 B1.
Systemic lupus erythematosus (SLE) and Rheumatoid arthritis are chronic inflammatory disease of multifactorial aetiology, characterized by inflammation and damage of various tissues and organs. Current treatments of the disease are mainly based on immunosuppressive drugs. Although these treatments have reduced mortality and morbidity, they cause a non-specific immune suppression. To avoid these side effects, alternative therapeutic strategies, which consist for example in specific T cell targeting using autoantigen-derived peptides identified as sequences encompassing major epitopes have been suggested (Monneaux and Muller (2007), Adv. Exp. Med. Biol. 601:105-12; Monneaux and Muller (2004), Autoimmun. Rev. 3(1):16-24).